Monoclonal gammopathy of undetermined significance (MGUS) is present in 3% of people more 70 years of ag e. It is our hypothesis that although both multiple myeloma (MM) and MGUS are characterized by the presence of abnormal bone marrow (BM) plasma cells, they are biologically different. The mechanisms of why some patients transform from MGUS to MM are poorly understood. It is clear from our initial studies that abnormal plasma cells can circulate and proliferate in the peripheral blood (PB) of patients with MM. However, their remains debate as to whether the disease is propagated at the plasma cell level versus a precursor B-cell. This proposal will involve the collaboration of two laboratories to examine cells from split-samples of the PB and BM of patients with MM and MGUS to gain a better understanding of how frequently circulating plasma cells and clonally-related cells are found in these diseases and the immunologic and molecular characteristics of these cells. PBMNC from patients with MGUS and MM will be analyzed for plasma cells and precursor B-cells by two-color immunofluorescence microscopy, multiparameter DNA content flow cytometry (FC), and three-color immunophenotyping by FC. An allele-specific oligonucleotide (ASO) will be used in a sensitive and tumor-specific polymerase chain reaction (PCR) technique developed in our laboratory to identify and quantitate malignant plasma cells and clonally-related cells. Cells sorted by various size, immunophenotypic, and DNA content parameters will be examined with the ASO-PCR technique to learn the specific characteristics of the malignant clone. Cells will also be sorted by FC into CD38+ and CD38- fractions and examined by reverse transcript PCR to identify clonally related transcripts that are derived from early B-cell precursors. We aim to learn 1) Do precursor cells or plasma cells circulate in the pB of patients with MGUS? 2) Can clonal cells be demonstrated in the pB of patients with MM or MGUS when no plasma cells are found thus providing evidence for circulating precursor cells? 3) If precursor cells are found, what is their molecular and immunophenotype? and 4) Can monoclonal plasma cells be grown in stromal cell cultures or in SCID mice from sorted cell populations? These results will better define the role of the PB cells in producing and maintaining malignant cells. The study of both MGUS and MM patients provides an opportunity to better understand the similarities and differences in circulating cells found in these two diseases and their role in disease progression.